The GLUT2 facilitated glucose transporter isoform is a membrane protein present in the pancreatic .beta.-insulin-secreting cells, the basolateral membrane of intestinal and kidney absorptive cells, in hepatocytes and in a subset of neurons (21,31,44). In these cells, GLUT2 catalyzes the transepithelial transport of glucose. In pancreatic islets, GLUT2 allows a rapid equilibration of glucose between the extracellular space and the interior of the cells and it may play a crucial role in the glucose signaling mechanism leading to insulin secretion (43). However, the relative importance of GLUT2 in the sensing of the .beta.-pancreatic cells to glucose remains debated. In human .beta.-cells, the level of expression of GLUT2 is low and the intracellular glucokinase activity seems to be the rate-limiting step in the glycolytic pathway (5,11). On the other hand, insulinoma cells that had lost their normal glucose responsiveness have low GLUT2 content, but some glucose sensitivity may be recovered after reintroducing GLUT2 expression through stable transfection of these cells (10,16). Furthermore, transgenic mice that express GLUT2 antisense RNAs driven by the insulin promoter led to an 80% reduction in GLUT2 which was paralleled by a decreased glucose-induced insulin secretory response and by the onset of diabetes (48). These observations are critical since several experimental models of diabetes have shown that GLUT2 expression is dramatically reduced specifically in the pancreatic .beta.-cells, and that this mechanism could participate to the onset of the disease (18,29,30,32,45-47). Therefore, while GLUT2 levels are unchanged or even upregulated in several tissues such as the liver and the intestine during the hyperglycemic conditions observed in diabetes, the same gene undergoes a drastic dysregulation only in the pancreatic islets.
A fragment of the murine GLUT2 promoter has been cloned and shown to be glucose-responsive when transfected into differentiated insulin-producing cells or into hepatocytes (35,36,52). Important cis-regulatory sequences were identified within this promoter region including a functionally responsive PDX-1 element, a cyclic AMP responsive element, and three cis elements termed GTI, GTII and GTIII (3,36,53). The presence of GTI, II and III are both sufficient and necessary to confer pancreatic-specific expression to a reporter gene in vitro or in vivo, using a transgenic mice approach (3,51). GTI and GTIII have been previously shown to bind distinct, but ubiquitously expressed trans-acting factors.